- Email: [email protected]
3 receptor antagonist haloperidol
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Repeated but not acute treatment with Δ9-tetrahydrocannabinol disrupts prepulse inhibition of the acoustic startle: Reversal by the dopamine D2/3 receptor antagonist haloperidol Benjamin B. Tourniera, Nathalie Ginovarta,b,n a
University Department of Psychiatry, University of Geneva, Geneva, Switzerland Clinical Neurophysiology and Neuroimaging Unit, Department of Psychiatry, University Hospitals of Geneva, Chemin du Petit Bel-Air 2, CH-1225 Geneva, Switzerland
b
Received 21 October 2013; received in revised form 11 March 2014; accepted 27 April 2014
KEYWORDS
Abstract
THC; Prepulse inhibition; Dopamine; D2/3-receptor; Haloperidol
Cannabis produces cognitive dysfunctions that resemble those of schizophrenia; yet the neurobiological substrate of this similarity remains unclear. Schizophrenia patients show deficits in prepulse inhibition (PPI) of the acoustic startle reflex (ASR), an operational measure of the information-processing abnormalities that may underlie the cognitive and positive symptoms of the disease. However, the effect of cannabis on PPI remains poorly understood, as data are often contradictory. Here, we investigated the effect of acute and repeated treatment with Δ9-tetrahydrocannabinol (THC), the main psychoactive constituent of cannabis, on PPI in rats, and the role of dopamine D2/3-receptor blockade in this effect. PPI and ASR were sequentially measured after the first and the last dose of a 21-days treatment with THC (1 mg/ kg/day) or vehicle and at 1-week following discontinuation of treatment. The effect of haloperidol (0.1 mg/kg) on THC-induced PPI alteration was also evaluated. Chronic, but not acute, THC treatment produced significant reductions in PPI that were normalized back to control values within one-week of THC discontinuation. The THC-induced gating deficits were observed in the absence of ASR change and were reversed by the D2/3-receptor antagonist haloperidol. Chronic THC exposure induced PPI disruptions that emerged only following repeated administrations, suggesting that time-dependent neuroadaptations within the DA mesolimbic system are involved in the disruptive effects of THC on sensorimotor gating. These gating deficits were transient and appeared to be dependent on an overactivity of
n Corresponding author at: Clinical Neurophysiology and Neuroimaging Unit, Department of Psychiatry, University Hospitals of Geneva, Chemin du Petit Bel-Air 2, CH-1225 Geneva, Switzerland. Tel.: +41 22 305 53 91; fax: +41 22 305 53 75. E-mail address: [email protected] (N. Ginovart).
http://dx.doi.org/10.1016/j.euroneuro.2014.04.003 0924-977X/& 2014 Published by Elsevier B.V.
Please cite this article as: Tournier, B.B., Ginovart, N., Repeated but not acute treatment with Δ9-tetrahydrocannabinol disrupts prepulse inhibition of the.... European Neuropsychopharmacology (2014), http://dx.doi.org/10.1016/j.euroneuro.2014.04.003
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B.B. Tournier, N. Ginovart D2/3-receptor-mediated dopamine signaling, highlighting a potential role for D2/3-receptors in the propsychotic action of THC. & 2014 Published by Elsevier B.V.
1.
Introduction
The psychotropic effects of cannabis are produced mainly through activation of CB1 receptors (CB1R) by Δ9-tetrahydrocannabinol (THC), the major psychoactive constituent of cannabis. Although considerable debate still remains in the fields, several lines of evidence suggest a potential relationship between cannabis use and schizophrenia. Besides inducing a state of euphoria and relaxation, cannabis use can lead to transient psychotic episodes in susceptible individuals, can produce exacerbation and relapse of psychotic symptoms in schizophrenia patients, and is associated with an earlier onset of psychotic illness (review in D'Souza et al., 2009). Human studies examining regular consumers also indicated that chronic cannabis use affects cognitive functioning, with impairments in the domains of attention, memory and executive functioning (Lundqvist, 2005) that appear to overlap on a number of aspects with the cognitive deficits of schizophrenia (Fletcher and Honey, 2006). Those detrimental effects of cannabis on cognitive performance appear to worsen with the duration and quantity of cannabis use (Solowij et al., 1995). However, whether they are reversible or whether they persist after prolonged abstinence from the drug has been a matter of controversy (Pope et al., 2001; Solowij, 1995). While there is much current interest in possible similarities between cognitive effects of cannabis use and those of schizophrenia, the neurobiological substrates of such cognitive effects of cannabis remain unclear. Prepulse inhibition (PPI) of the acoustic startle reflex (ASR) is an operational measure of sensorimotor gating and refers to the natural reduction in the magnitude of the startle reaction caused by a loud auditory stimulus when it is immediately preceded by a weak prestimulus. PPI is thought to index the activity of preattentive filter mechanisms that are central to gate out irrelevant and distracting sensory information (Braff and Geyer, 1990). A disruption of these normal gating mechanisms is believed to produce an overload of sensory information to be processed, leading to attentional impairments and subsequent cognitive disorganization (Braff and Geyer, 1990). Deficits in PPI have consistently been reported in patients with schizophrenia (review in Braff et al., 2001), and have been shown to correlate with measures of perceptual and reasoning disturbances (Perry et al., 1999), of greater distractability (Karper et al., 1996) and with aspects of hallucinations (Kumari et al., 2008), supporting the view that deficient sensory gating may underlie some aspects of the positive and cognitive symptoms of the disease (Vollenweider and Geyer, 2001). Relatively few human studies have investigated the impact of cannabis consumption on PPI and have produced mixed results. While some studies showed no PPI alteration in chronic cannabis users (Mathias et al., 2011; Quednow et al., 2004), others found evidence of PPI deficits that were correlated with the duration of cannabis use (Kedzior and Martin-Iverson, 2006), or that were observable only when
using a PPI paradigm where the prepulse was conscientiously attended instead of being ignored (Kedzior and Martin-Iverson, 2007; Scholes and Martin-Iverson, 2009; Scholes-Balog and Martin-Iverson, 2011). The reasons for these discrepancies remain unclear but may be related to between-study differences in the total duration, the age at onset of use, the amount, strength and frequency of cannabis used, or the time elapsed between the last cannabis use and PPI testing, which could range from practically none (Kedzior and Martin-Iverson, 2006; Scholes and Martin-Iverson, 2009, 2011) to a few hours (Mathias et al., 2011) or a few days (Quednow et al., 2004). Human studies thus suffers from inherent limitations due to the great heterogeneity of cannabis use pattern and history among users, as well as to the existence of other substance abuse or dependence (Scholes and Martin-Iverson, 2009; Scholes-Balog and Martin-Iverson, 2011) that may affect PPI performance in cannabis users. As PPI is a robust crossspecies phenomenon (Swerdlow et al., 2001), research in experimental animals offers the opportunity for controlled investigation of the direct impact of cannabinoid exposure on PPI. To our knowledge, only one study has investigated the effects of chronic THC exposure on PPI in rodents and failed to detect any effect of the drug at either 7 days or 18 days of THC treatment (Long et al., 2010a). However, a major limitation of this study is that, because it examined several behavioral tests in the same experiment, all mice had also received an acute injection of the NMDA antagonist MK-801 just prior to PPI testing on day 7, and had been subjected to a behavioral test of anxiety just prior to PPI testing on day 18. This makes a definite interpretation of the direct THC effects on PPI difficult as both NMDA receptor blockade and the glucocorticoid stress response that is observed in the anxiety test (File et al., 1988) can both affect PPI (Nespor and Tizabi, 2008; Richter et al., 2011). In light of the paucity of studies using THC, the goal of the present study was to investigate the effects of acute and chronic treatment with THC on PPI. As the duration of drug discontinuation period may influence PPI, measures of PPI were also performed at 1-week following drug discontinuation. Moreover, as recent data from our group indicated that chronic THC treatment increases the availability and functional sensitivity of dopamine (DA) D2/3 receptors (D2/ 3R) within the mesolimbic system (Ginovart et al., 2012), we investigated whether potential THC-induced PPI deficits were sensitive to D2/3R blockade using haloperidol.
2. 2.1.
Experimental procedures Animals and drug treatments
Male Sprague-Dawley rats, weighing 250–275 g, were obtained from Janvier Laboratories (Le Genest-Saint-Isle, France) and housed in a 12:12 h light–dark cycle with food and water ad libitum. THC (Tocris
Please cite this article as: Tournier, B.B., Ginovart, N., Repeated but not acute treatment with Δ9-tetrahydrocannabinol disrupts prepulse inhibition of the.... European Neuropsychopharmacology (2014), http://dx.doi.org/10.1016/j.euroneuro.2014.04.003
Repeated but not acute treatment with Δ9-tetrahydrocannabinol disrupts prepulse inhibition of the acoustic startle: Reversal by the dopamine D2/3 receptor antagonist haloperidol Biosciences, UK) was dissolved in 0.9% saline/ethanol/cremophor (18:1:1) and administered intraperitonally (i.p.) at 1 mg/kg/day for 21 days. Control rats received the vehicle (VEH) solution. Haloperidol (Janssen-Cilag, Switzerland) was injected i.p. at 0.1 mg/kg. Experiments were performed in accordance with the Swiss Federal Law on animal care and were approved by the Ethical Committee on Animal Experimentation of the Canton of Geneva.
2.2.
Experimental procedure
In a first experiment, a total of 16 rats were treated with 21 daily injections of THC (n=8) or VEH (n=8). In each animal, PPI was measured at 30 min following the 1st and the 21st injection of THC or VEH and at 7 days following the last treatment dose. In a second experiment, rats were treated with 21 daily injections of THC (n=16) or VEH (n=16). Ten minutes prior to the last injection, animals in each treatment group received an i.p. challenge dose of either haloperidol (0.1 mg/kg) or saline vehicle. All animals were tested for PPI at 30 min following the last treatment dose of THC or VEH. The dose of haloperidol was determined based on its ability to block 80–90% of the D2/3R in the rat brain without inducing catalepsy (Wadenberg et al., 2001).
2.3.
Startle response measurement
PPI was measured using two identical Startle Response Systems (TSE, Bad Homburg, Germany). Each system consisted of a soundattenuated and ventilated chamber equipped with a movementsensitive measuring platform and two loudspeakers providing the background noise and acoustic stimuli. During the measurement, animals were individually placed into a wire-mesh cage (22.5 cm 8.0 cm 8.5 cm) resting on the measuring platform and located at a distance of 4 cm from the loudspeakers. Startle responses, as reflected by the movement of animals in the cage in response to the acoustic stimuli, were detected by a piezoelectric motion sensor mounted in the platform. The administration of stimuli and startle response recording were controlled by the TSE software. Rats were habituated to this apparatus for two consecutive days before each PPI test session (day 1: 10 min; day 2: 30 min). PPI test sessions started with a 10-min acclimatization to a 70-dB background noise to accustom the rat to the chamber. Following the acclimatization period, the test session was presented in 3 blocks. The first (B1) and last (B3) blocks consisted of five pulse-alone trials (120 dB, 40 ms) with an average inter-trial interval (ITI) of 20 s (10–30 s). Amplitude of the ASR in pulse alone trials was defined as the peak amplitude of the response elicited during the 100 ms period after onset of the pulse stimulus. Amplitudes of the ASR obtained in B1 and B3 were used to measure startle habituation as follows: [1-(startle amplitude in B3/startle amplitude in B1)] 100%. The second block (B2) consisted of 72 trials presented in a random order in order to measure PPI: 24 trials with a pulse-alone stimulus (120 dB, 40 ms), 12 trials with no stimulus (70-dB background noise, 200 ms), three types (3 12) of prepulse-and-pulse trials which included a 20-ms prepulse (75, 80, or 85-dB) followed 100 ms later by a 120-dB pulse stimulus. The mean ITI was 20 s. Startle responses were measured for 100 ms after the onset of the pulse stimulus within trials. For each type of trial, startle amplitudes were averaged across 12 trials. In B2, the magnitude of PPI was calculated as a percent inhibition of the startle amplitude in the pulse-alone trial (treated as 100%) according to the formula: [1-(startle amplitude in prepulse-and-pulse trials/startle amplitude in pulse-alone trials)] 100%.
2.4.
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Statistical analysis
In the first experiment, amplitudes of the startle reflex in B1 and in B2 as well as PPI were analyzed by repeated one-way ANOVA with treatment as a between-subjects factor and test day as a withinsubjects factor. PPI was analyzed by repeated two-way ANOVAs with treatment and prepulse intensity as between-subject factors and test day as within-subject factor. Startle habituation was analyzed by repeated two-way ANOVA with treatment and blocks (B1 and B3) as between-subject factors and test day as within-subject factor. In the second experiment, amplitudes of the startle reflex measured in B1 and in B2 were analyzed by a two-way ANOVA with chronic treatment (THC or VEH) and acute challenge treatment (Haloperidol or Saline) as between-subject factors. Startle habituation was analyzed by a repeated two-way ANOVA with blocks (B1 and B3) as within-subject factor and chronic and challenge treatments as between-subject factors. PPI were analyzed by a threeway ANOVA with chronic treatment, challenge treatment and prepulse intensity as between-subject factors. Post-hoc comparisons were performed using the LSD Fisher test. All analyses were performed using Statistica 11.0 (StatSoft Inc., USA). Data are expressed as mean7SEM of 8 animals per group.
3.
Results
3.1. Acute and chronic effects of THC on prepulse inhibition 3.1.1. Startle habituation As shown in Figure 1, comparing the startle response in the first block (B1) and the last block (B3) within sessions revealed a clear habituation effect (B14B3) both in the vehicle and in the THC-treated group. The main effect of blocks was highly significant (F1,42 = 118.37; po0.001) and was independent of the test day (block test day: F2,42 = 0.37; p40.05), indicating that startle reflex habituation was similar in sessions over the course of study. There was neither a main effect of treatment on habituation (F1,42 = 2.20; p40.05) nor any of its interactions (treatment habituation, F1,42 = 2.26; p40.05; treatment test day, F2,42 = 1.17; p40.05), indicating that habituation did not differ between THC-treated rats and their vehicletreated controls (meanvehicle-treated = 50.774.0%; meanTHCtreated = 52.373.90%). 3.1.2. Startle reactivity There was no main effect of group (F1,28 = 0.04; p40.05) or test day (F2,28 = 0.14; p40.05) on startle amplitudes in B1 (Figure 1A). Similarly, analysis of the startle amplitudes elicited on pulse alone trials in B2 did not reveal a significant main effect of group (F1,28 = 0.46; p40.05) or test day (F2,28 = 0.18; p40.05), indicating that THC treatment did not change startle reactivity when compared to vehicle and that this lack of treatment effect was preserved over the course of THC treatment (Figure 2A). 3.1.3. Prepulse inhibition Figure 2B–D shows the effect of acute and repeated administrations of vehicle or THC on PPI at different prepulse intensity levels (e.g. 75, 80 and 85 dB). A significant main effect of prepulse intensity on PPI was observed (F2,42 = 21.85; po0.001), with increasing prepulse intensities
Please cite this article as: Tournier, B.B., Ginovart, N., Repeated but not acute treatment with Δ9-tetrahydrocannabinol disrupts prepulse inhibition of the.... European Neuropsychopharmacology (2014), http://dx.doi.org/10.1016/j.euroneuro.2014.04.003
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B.B. Tournier, N. Ginovart
Figure 1 Acute and chronic effects of THC or its vehicle (VEH) on amplitude of the ASR (A) and startle habituation (B). Amplitude of the ASR during the first block and startle habituation were measured at 30 min following the first (day 1) and last (day 21) dose of a 21-days daily treatment with THC (1 mg/kg/day) or vehicle (VEH), and at 7 days after cessation of treatment (day 28). On each testing day, startle habituation (in %) was calculated by comparing the startle amplitude measured in a first (B1) and in a third (B3) block of five consecutive 120 dB pulse alone trial as follows: [1-(startle amplitude in B3/startle amplitude in B1)] 100%. Data represent mean7SEM of 8 animals per group. While there was a marked habituation of the startle response (main effect of block, F1,42 =118.37; po0.001), there was no significant group difference in startle habituation.
eliciting higher levels of PPI, which is a standard feature of PPI (Braff et al., 2001). Repeated two-way ANOVA also revealed a main effect of test day on PPI (F2,84 = 7.80; po0.05) that was dependent of the treatment group (treatment test day: F2,84 = 15.28; po0.001). There was also a significant group test day prepulse intensity interaction (F4,84 = 2.51; po0.05). LSD post-hoc tests revealed that the THC-treated group had significantly lower PPIs than the VEH-treated control group on the 21st day of chronic treatment but not on the first day of acute THC treatment at the prepulse intensities of 75 dB (po0.01; Figure 2B), 80 dB (po0.0001; Figure 2C) and 85 dB (po0.001; Figure 2D). Importantly, whatever the prepulse intensity used, group differences in PPI were abolished at 7 days following the cessation of treatment (Figure 2B–D).
3.2. Effect of haloperidol on THC-induced PPI deficits Two-way analysis of variance did not reveal significant effect of either chronic treatment with THC or acute challenge treatment with haloperidol on the startle reflex amplitude measured in B1 (THC treatment: F1,28 =1.00, p40.05; challenge treatment: F1,28 =2.23, p40.05). Similarly, there was also no significant effect of either chronic THC or acute haloperidol treatment on startle reactivity measured in B2 (THC treatment: F1,28 =0.36, p40.05; haloperidol treatment: F1,28 =2.27, p40.05; Figure 3A). However, startle response differed significantly between B1 and B3 (F1,28 =88.32; po0.001), independently of treatments (block chronic treatment challenge treatment: F1,28 =1.08, p40.05). Chronic treatment with THC or challenge treatment with haloperidol did not modify this startle habituation effect, as shown by the lack of effect of either treatment on habituation (chronic treatment: F1,28 =3.01, p40.05; challenge treatment: F1,28 =0.39, p40.05; chronic treatment challenge treatment: F1,28 =0.88, p40.05; Figure 3B).
The analysis performed on PPI showed significant main effects of both chronic THC (F1,84 =22.49; po0.001) and acute challenge with haloperidol (F1,84 =10.80, po0.01). Three-way ANOVA revealed a significant effect of prepulse intensities (F2,84 =34.33; po0.001) on PPI and a THC treatment haloperidol treatment prepulse intensity interaction (F2,84 =3.11; po0.05). Post-hoc analysis demonstrated that, similarly to the first experiment, chronic THC treatment led to significant PPI disruptions at the 75 dB (po0.001), 80 dB (po0.01) and 85 dB (po0.05) prepulse intensity levels (Figure 3C–E). Importantly, when compared to their respective saline-treated controls, an acute challenge dose of haloperidol had no effect on PPI in VEH-treated animals but significantly increased PPI in THC-treated animals at the 75 dB (po0.0001; Figure 3C) and 80 dB (po0.01; Figure 3D) prepulse intensity levels. Haloperidol (HAL) did completely reversed THC-induced PPI reductions at all prepulse intensities, as evidenced by the lack of significant difference between the THC+HAL and VEH +Saline groups at the 75 dB (p=0.54; Figure 3C), 80 dB (p=0.58; Figure 3D) and 85 dB (p=0.54; Figure 3E) prepulse intensities.
4.
Discussion
To our knowledge, this is the first study to investigate the effects of THC on PPI during acute and chronic drug treatment and following drug discontinuation, without potential confounders. Our findings show that repeated, but not acute, treatment with THC leads to deficits in sensorimotor gating that fully reverse within one week of THC discontinuation. Importantly, the disruptive effects of THC on PPI were observed in the absence of changes in the startle response and were reversed by the potent D2/3R antagonist haloperidol. This suggests that time-dependent neuroadaptations within the DA mesolimbic system may be involved in the PPI deficits that develop during chronic THC treatment.
Please cite this article as: Tournier, B.B., Ginovart, N., Repeated but not acute treatment with Δ9-tetrahydrocannabinol disrupts prepulse inhibition of the.... European Neuropsychopharmacology (2014), http://dx.doi.org/10.1016/j.euroneuro.2014.04.003
Repeated but not acute treatment with Δ9-tetrahydrocannabinol disrupts prepulse inhibition of the acoustic startle: Reversal by the dopamine D2/3 receptor antagonist haloperidol
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Figure 2 Acute and chronic effects of THC or its vehicle (VEH) on prepulse inhibition (PPI) of the acoustic startle reflex (ASR). The amplitude of the ASR during the second block (A) and PPI at prepulse intensities of 75 dB (B), 80 dB (C) and 85 dB (D) were measured at 30 min following the first (day 1) and last (day 21) dose of a 21-days daily treatment with THC (1 mg/kg/day) or vehicle (VEH), and at 7 days after cessation of treatment (day 28). Data are presented as mean7SEM of 8 animals per group. Significantly different from the respective VEH-treated group at nnpo0.01, and nnnpo0.001, using a two-way ANOVA followed by a LSD post-hoc test.
Our finding of a lack of effect of a single dose of 1-mg/kg THC on PPI is consistent with several (Boucher et al., 2007; Long et al., 2010b; Malone and Taylor, 2006), but not all (Long et al., 2010a; Nagai et al., 2006), previous studies which also failed to detect any significant effect of acute THC on sensorimotor performance in rodents, regardless of dosage. As mentioned in the introduction, previous work on the effects of chronic treatment with THC on PPI in rodents is limited to one study (Long et al., 2010a), in which no effect of THC was found. Similar chronic studies using the synthetic cannabinoid agonist WIN55,212-2 have however been reported but with inconsistent findings, with some studies reporting persistent PPI deficits (Schneider et al., 2005; Wegener and Koch, 2009), while others found no effect of the drug on PPI performance (Bortolato et al., 2005; Spano et al., 2010). Besides a strain- or speciesdependent effect of cannabinoids, it has been suggested that between-study difference in the age of initiation of cannabinoid treatment (i.e. adolescence vs. adult period) may be critical for PPI deficits to occur, with adolescent rats being more vulnerable than adults to the PPI disruptive effect of cannabinoid agonists (review in Schneider, 2008). However, another study challenged this view by showing
that chronic treatment with AM404, a selective reuptake and degradation inhibitor of the endogenous cannabinoid anandamide, led to PPI deficits when administered to adult mice (Fernandez-Espejo and Galan-Rodriguez, 2004). Moreover, it is noteworthy that most of the chronic cannabinoid research on PPI in rodents has been directed mainly toward WIN55,212-2, which is structurally unrelated to THC and shows different profiles of CB1R (Lauckner et al., 2005) and non-CB1R binding (Breivogel et al., 2001). Thus while the pharmacological effects produced by WIN55,212-2 and THC display considerable overlap, their different ability to activate different receptors and subsequent downstream signaling may hamper a direct and systematic extrapolation of the effects obtained with one agonist to the other. Consistent with this, different and sometimes even opposing effects of WIN55,212-2 and THC on cellular (Galanopoulos et al., 2011) and neurobehavioral (Patel and Hillard, 2006) responses have been reported. Contrasting with its lack of acute effect, our data showed that when administered daily for 21 consecutive days, relatively low doses of THC impaired PPI performance, suggesting that THC promotes neuroadaptations within the neural circuit regulating sensorimotor gating that develops
Please cite this article as: Tournier, B.B., Ginovart, N., Repeated but not acute treatment with Δ9-tetrahydrocannabinol disrupts prepulse inhibition of the.... European Neuropsychopharmacology (2014), http://dx.doi.org/10.1016/j.euroneuro.2014.04.003
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B.B. Tournier, N. Ginovart
Figure 3 Effect of an acute treatment with haloperidol (0.1 mg/kg; i.p.) on prepulse inhibition (PPI). The amplitude of the startle response (ASR) during the second block (A), startle habituation (B) and PPI at prepulse intensities of 75 dB (C), 80 dB (D) and 85 dB (E) were measured at 30 min following the last dose of a 21-days daily treatment with THC (1 mg/kg/day) or vehicle (VEH). Ten minutes prior to the last treatment dose, both the VEH-treated and THC-treated rats received an i.p. administration of either haloperidol (HAL; 0.1 mg/kg) or saline vehicle (n =8). Data are presented as mean7SEM of 8 animals per group. Significantly different from the VEH-Saline group at npo0.05, nnpo0.01, nnnpo0.001 and significantly different from the THC–Saline group at ⌘⌘⌘ po0.01, ⌘⌘po0.01 using a three-way ANOVA followed by a LSD post-hoc test.
during the course of repeated drug administration. However, chronic THC only had a transient detrimental effect on sensorimotor gating function as, while observed at 30 min after the last dose, PPI deficits had completely recovered within 7 days after treatment had ceased. These data suggest that the functional alterations produced by THC are quickly reversible following treatment cessation and may be related to a drug residue effect during the few hours to the few days following THC dosing rather than to a permanent neurotoxic effect of the drug. Indeed, due to its high lipophilicity and sequestration in fat, the tissue elimination half-life of THC is slow, being estimated to be from about 16 h (Nahas, 1972) to as long as 5 days (Kreuz and Axelrod, 1973) in rats. Our data also suggest that the duration of time elapsed between last cannabis use and PPI measurement is critical for measuring cannabis-related effects on sensorimotor gating and may be a main reason for the inconsistent findings previously reported regarding the influence of cannabis consumption on PPI in chronic human users. Indeed, the duration of cannabis abstinence period prior to PPI testing widely differed between previous
studies, ranging from practically none in studies reporting cannabis-related PPI deficits (Kedzior and Martin-Iverson, 2006; Scholes and Martin-Iverson, 2009; Scholes-Balog and Martin-Iverson, 2011) to a few hours to a few days in studies reporting no alteration (Mathias et al., 2011; Quednow et al., 2004). Moreover, a time-dependent decreasing effect of THC on PPI following discontinuation would be consistent with, and may shed light on, the correlation previously reported between PPI alterations and the recency of cannabis use in chronic users (Scholes and Martin-Iverson, 2009). As abnormalities in pre-attentive information processing, as measured by PPI deficits, are thought to contribute to impaired cognitive functioning, the time-dependency of THC-induced PPI alterations observed here is consistent with studies indicating that chronic cannabis consumption in human is associated with a decline in cognitive performance that develop gradually with prolonged cannabis use and worsen with years of use (Solowij et al., 2002), but last only for a limited period beyond the immediate hours of intoxication (Schreiner and Dunn, 2012). Taken together with prior human studies, our results do not support the
Please cite this article as: Tournier, B.B., Ginovart, N., Repeated but not acute treatment with Δ9-tetrahydrocannabinol disrupts prepulse inhibition of the.... European Neuropsychopharmacology (2014), http://dx.doi.org/10.1016/j.euroneuro.2014.04.003
Repeated but not acute treatment with Δ9-tetrahydrocannabinol disrupts prepulse inhibition of the acoustic startle: Reversal by the dopamine D2/3 receptor antagonist haloperidol idea of a long-term persistence of neuropsychological dysfunctioning following cessation of chronic cannabis use. A large body of evidence indicates that the central DA system contributes to the regulation of PPI, although there is also evidence for a role of the serotonin and glutamatergic system as well (Geyer et al., 2001; Swerdlow et al., 2001). In rodents, PPI is disrupted by acute treatment with direct or indirect DA agonists (Mansbach et al., 1988), as well as with selective D2-receptor (D2R) agonists (Weber et al., 2010), and these effects can be reversed by D2R antagonists. Moreover, while the activation of D2R in the mesolimbic DA system, especially in the nucleus accumbens (Wan and Swerdlow, 1993), appears essential to the DAergic regulation of PPI, emerging evidence demonstrates that stimulation of accumbal D3R also contributes to this effect (Chang et al., 2012). The present study showed that the PPI deficit induced by chronic THC treatment can be reversed by a low, non-cataleptic dose, of the D2/3R antagonist haloperidol, suggesting that an overactivity of D2/3R-mediated DA transmission in the mesoaccumbal system likely contributes to the gating-disruptive effects of THC. This hypothesis is consistent with recent data from our group showing that chronic THC increases the density and functional sensitivity of D2/3R in the nucleus accumbens (Ginovart et al., 2012). In this latter study, the hypersensitization of postsynaptic D2/3R in nucleus accumbens was accompanied by a concomitant hypoactivity of presynaptic DA signaling, making it difficult to predict the overall net effect of THC treatment on DA transmission. The current results support the view that chronic THC produces a net facilitation of D2/3R-mediated DA signaling in the mesoaccumbal system. Collectively, these findings show considerable overlap with the psychopathogical and neurochemical changes associated with schizophrenia. PPI disruptions have been widely reported in schizophrenia (review in Braff et al., 2001). Moreover, the symptoms of psychosis are thought to result from an excess of DA signaling in the mesolimbic system (Davis et al., 1991), and two independent meta-analyses provide evidence for an increased density of striatal D2/3R in schizophrenia (Kestler et al., 2001; Weinberger and Laruelle, 2002), lending support to the view that an overactivity of D2/3R may be critically involved in the PPI deficits seen in schizophrenia (Swerdlow et al., 1991). The overlap between PPI and D2/3R abnormalities induced by chronic THC and those previously reported in schizophrenia may improve our understanding of the mechanism underlying the propsychotic action of THC. In summary, our data indicate that chronic but not acute exposure to THC leads to the development of PPI deficits that can be reversed by D2/3R blockade, indicating that an overactivity of D2/3R function contributes to the gating-disruptive effects of the drug. THC-induced PPI deficits were fully normalized within the first week after THC discontinuation, indicating that the drug only has transient detrimental effects on sensorimotor gating ability. These findings add to the emerging evidence that chronic THC exposure increases DA function in brain, highlighting a potential role for D2/3R in the propsychotic effect of the drug.
Role of funding sources Funding for this study was provided by Swiss National Science Foundation (SNFS) grant 31003 A-122352 to N.G.; the SNFS had no
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further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.
Contributors B.B.T. performed behavioral tests, statistical analyses, and contributed to the first draft of the manuscript. N.G. wrote the protocol, supervised the experimental design and execution, and wrote the manuscript. All authors read and approved the final manuscript.
Conflict of interest The authors certify that there is no actual or potential conflict of interest in relation to this article.
Acknowledgment None.
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Please cite this article as: Tournier, B.B., Ginovart, N., Repeated but not acute treatment with Δ9-tetrahydrocannabinol disrupts prepulse inhibition of the.... European Neuropsychopharmacology (2014), http://dx.doi.org/10.1016/j.euroneuro.2014.04.003
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Repeated but not acute treatment with Δ9-tetrahydrocannabinol disrupts prepulse inhibition of the acoustic startle: Reversal by the dopamine D2/3 receptor antagonist haloperidol Benjamin B. Tourniera, Nathalie Ginovarta,b,n a
University Department of Psychiatry, University of Geneva, Geneva, Switzerland Clinical Neurophysiology and Neuroimaging Unit, Department of Psychiatry, University Hospitals of Geneva, Chemin du Petit Bel-Air 2, CH-1225 Geneva, Switzerland
b
Received 21 October 2013; received in revised form 11 March 2014; accepted 27 April 2014
KEYWORDS
Abstract
THC; Prepulse inhibition; Dopamine; D2/3-receptor; Haloperidol
Cannabis produces cognitive dysfunctions that resemble those of schizophrenia; yet the neurobiological substrate of this similarity remains unclear. Schizophrenia patients show deficits in prepulse inhibition (PPI) of the acoustic startle reflex (ASR), an operational measure of the information-processing abnormalities that may underlie the cognitive and positive symptoms of the disease. However, the effect of cannabis on PPI remains poorly understood, as data are often contradictory. Here, we investigated the effect of acute and repeated treatment with Δ9-tetrahydrocannabinol (THC), the main psychoactive constituent of cannabis, on PPI in rats, and the role of dopamine D2/3-receptor blockade in this effect. PPI and ASR were sequentially measured after the first and the last dose of a 21-days treatment with THC (1 mg/ kg/day) or vehicle and at 1-week following discontinuation of treatment. The effect of haloperidol (0.1 mg/kg) on THC-induced PPI alteration was also evaluated. Chronic, but not acute, THC treatment produced significant reductions in PPI that were normalized back to control values within one-week of THC discontinuation. The THC-induced gating deficits were observed in the absence of ASR change and were reversed by the D2/3-receptor antagonist haloperidol. Chronic THC exposure induced PPI disruptions that emerged only following repeated administrations, suggesting that time-dependent neuroadaptations within the DA mesolimbic system are involved in the disruptive effects of THC on sensorimotor gating. These gating deficits were transient and appeared to be dependent on an overactivity of
n Corresponding author at: Clinical Neurophysiology and Neuroimaging Unit, Department of Psychiatry, University Hospitals of Geneva, Chemin du Petit Bel-Air 2, CH-1225 Geneva, Switzerland. Tel.: +41 22 305 53 91; fax: +41 22 305 53 75. E-mail address: [email protected] (N. Ginovart).
http://dx.doi.org/10.1016/j.euroneuro.2014.04.003 0924-977X/& 2014 Published by Elsevier B.V.
Please cite this article as: Tournier, B.B., Ginovart, N., Repeated but not acute treatment with Δ9-tetrahydrocannabinol disrupts prepulse inhibition of the.... European Neuropsychopharmacology (2014), http://dx.doi.org/10.1016/j.euroneuro.2014.04.003
2
B.B. Tournier, N. Ginovart D2/3-receptor-mediated dopamine signaling, highlighting a potential role for D2/3-receptors in the propsychotic action of THC. & 2014 Published by Elsevier B.V.
1.
Introduction
The psychotropic effects of cannabis are produced mainly through activation of CB1 receptors (CB1R) by Δ9-tetrahydrocannabinol (THC), the major psychoactive constituent of cannabis. Although considerable debate still remains in the fields, several lines of evidence suggest a potential relationship between cannabis use and schizophrenia. Besides inducing a state of euphoria and relaxation, cannabis use can lead to transient psychotic episodes in susceptible individuals, can produce exacerbation and relapse of psychotic symptoms in schizophrenia patients, and is associated with an earlier onset of psychotic illness (review in D'Souza et al., 2009). Human studies examining regular consumers also indicated that chronic cannabis use affects cognitive functioning, with impairments in the domains of attention, memory and executive functioning (Lundqvist, 2005) that appear to overlap on a number of aspects with the cognitive deficits of schizophrenia (Fletcher and Honey, 2006). Those detrimental effects of cannabis on cognitive performance appear to worsen with the duration and quantity of cannabis use (Solowij et al., 1995). However, whether they are reversible or whether they persist after prolonged abstinence from the drug has been a matter of controversy (Pope et al., 2001; Solowij, 1995). While there is much current interest in possible similarities between cognitive effects of cannabis use and those of schizophrenia, the neurobiological substrates of such cognitive effects of cannabis remain unclear. Prepulse inhibition (PPI) of the acoustic startle reflex (ASR) is an operational measure of sensorimotor gating and refers to the natural reduction in the magnitude of the startle reaction caused by a loud auditory stimulus when it is immediately preceded by a weak prestimulus. PPI is thought to index the activity of preattentive filter mechanisms that are central to gate out irrelevant and distracting sensory information (Braff and Geyer, 1990). A disruption of these normal gating mechanisms is believed to produce an overload of sensory information to be processed, leading to attentional impairments and subsequent cognitive disorganization (Braff and Geyer, 1990). Deficits in PPI have consistently been reported in patients with schizophrenia (review in Braff et al., 2001), and have been shown to correlate with measures of perceptual and reasoning disturbances (Perry et al., 1999), of greater distractability (Karper et al., 1996) and with aspects of hallucinations (Kumari et al., 2008), supporting the view that deficient sensory gating may underlie some aspects of the positive and cognitive symptoms of the disease (Vollenweider and Geyer, 2001). Relatively few human studies have investigated the impact of cannabis consumption on PPI and have produced mixed results. While some studies showed no PPI alteration in chronic cannabis users (Mathias et al., 2011; Quednow et al., 2004), others found evidence of PPI deficits that were correlated with the duration of cannabis use (Kedzior and Martin-Iverson, 2006), or that were observable only when
using a PPI paradigm where the prepulse was conscientiously attended instead of being ignored (Kedzior and Martin-Iverson, 2007; Scholes and Martin-Iverson, 2009; Scholes-Balog and Martin-Iverson, 2011). The reasons for these discrepancies remain unclear but may be related to between-study differences in the total duration, the age at onset of use, the amount, strength and frequency of cannabis used, or the time elapsed between the last cannabis use and PPI testing, which could range from practically none (Kedzior and Martin-Iverson, 2006; Scholes and Martin-Iverson, 2009, 2011) to a few hours (Mathias et al., 2011) or a few days (Quednow et al., 2004). Human studies thus suffers from inherent limitations due to the great heterogeneity of cannabis use pattern and history among users, as well as to the existence of other substance abuse or dependence (Scholes and Martin-Iverson, 2009; Scholes-Balog and Martin-Iverson, 2011) that may affect PPI performance in cannabis users. As PPI is a robust crossspecies phenomenon (Swerdlow et al., 2001), research in experimental animals offers the opportunity for controlled investigation of the direct impact of cannabinoid exposure on PPI. To our knowledge, only one study has investigated the effects of chronic THC exposure on PPI in rodents and failed to detect any effect of the drug at either 7 days or 18 days of THC treatment (Long et al., 2010a). However, a major limitation of this study is that, because it examined several behavioral tests in the same experiment, all mice had also received an acute injection of the NMDA antagonist MK-801 just prior to PPI testing on day 7, and had been subjected to a behavioral test of anxiety just prior to PPI testing on day 18. This makes a definite interpretation of the direct THC effects on PPI difficult as both NMDA receptor blockade and the glucocorticoid stress response that is observed in the anxiety test (File et al., 1988) can both affect PPI (Nespor and Tizabi, 2008; Richter et al., 2011). In light of the paucity of studies using THC, the goal of the present study was to investigate the effects of acute and chronic treatment with THC on PPI. As the duration of drug discontinuation period may influence PPI, measures of PPI were also performed at 1-week following drug discontinuation. Moreover, as recent data from our group indicated that chronic THC treatment increases the availability and functional sensitivity of dopamine (DA) D2/3 receptors (D2/ 3R) within the mesolimbic system (Ginovart et al., 2012), we investigated whether potential THC-induced PPI deficits were sensitive to D2/3R blockade using haloperidol.
2. 2.1.
Experimental procedures Animals and drug treatments
Male Sprague-Dawley rats, weighing 250–275 g, were obtained from Janvier Laboratories (Le Genest-Saint-Isle, France) and housed in a 12:12 h light–dark cycle with food and water ad libitum. THC (Tocris
Please cite this article as: Tournier, B.B., Ginovart, N., Repeated but not acute treatment with Δ9-tetrahydrocannabinol disrupts prepulse inhibition of the.... European Neuropsychopharmacology (2014), http://dx.doi.org/10.1016/j.euroneuro.2014.04.003
Repeated but not acute treatment with Δ9-tetrahydrocannabinol disrupts prepulse inhibition of the acoustic startle: Reversal by the dopamine D2/3 receptor antagonist haloperidol Biosciences, UK) was dissolved in 0.9% saline/ethanol/cremophor (18:1:1) and administered intraperitonally (i.p.) at 1 mg/kg/day for 21 days. Control rats received the vehicle (VEH) solution. Haloperidol (Janssen-Cilag, Switzerland) was injected i.p. at 0.1 mg/kg. Experiments were performed in accordance with the Swiss Federal Law on animal care and were approved by the Ethical Committee on Animal Experimentation of the Canton of Geneva.
2.2.
Experimental procedure
In a first experiment, a total of 16 rats were treated with 21 daily injections of THC (n=8) or VEH (n=8). In each animal, PPI was measured at 30 min following the 1st and the 21st injection of THC or VEH and at 7 days following the last treatment dose. In a second experiment, rats were treated with 21 daily injections of THC (n=16) or VEH (n=16). Ten minutes prior to the last injection, animals in each treatment group received an i.p. challenge dose of either haloperidol (0.1 mg/kg) or saline vehicle. All animals were tested for PPI at 30 min following the last treatment dose of THC or VEH. The dose of haloperidol was determined based on its ability to block 80–90% of the D2/3R in the rat brain without inducing catalepsy (Wadenberg et al., 2001).
2.3.
Startle response measurement
PPI was measured using two identical Startle Response Systems (TSE, Bad Homburg, Germany). Each system consisted of a soundattenuated and ventilated chamber equipped with a movementsensitive measuring platform and two loudspeakers providing the background noise and acoustic stimuli. During the measurement, animals were individually placed into a wire-mesh cage (22.5 cm 8.0 cm 8.5 cm) resting on the measuring platform and located at a distance of 4 cm from the loudspeakers. Startle responses, as reflected by the movement of animals in the cage in response to the acoustic stimuli, were detected by a piezoelectric motion sensor mounted in the platform. The administration of stimuli and startle response recording were controlled by the TSE software. Rats were habituated to this apparatus for two consecutive days before each PPI test session (day 1: 10 min; day 2: 30 min). PPI test sessions started with a 10-min acclimatization to a 70-dB background noise to accustom the rat to the chamber. Following the acclimatization period, the test session was presented in 3 blocks. The first (B1) and last (B3) blocks consisted of five pulse-alone trials (120 dB, 40 ms) with an average inter-trial interval (ITI) of 20 s (10–30 s). Amplitude of the ASR in pulse alone trials was defined as the peak amplitude of the response elicited during the 100 ms period after onset of the pulse stimulus. Amplitudes of the ASR obtained in B1 and B3 were used to measure startle habituation as follows: [1-(startle amplitude in B3/startle amplitude in B1)] 100%. The second block (B2) consisted of 72 trials presented in a random order in order to measure PPI: 24 trials with a pulse-alone stimulus (120 dB, 40 ms), 12 trials with no stimulus (70-dB background noise, 200 ms), three types (3 12) of prepulse-and-pulse trials which included a 20-ms prepulse (75, 80, or 85-dB) followed 100 ms later by a 120-dB pulse stimulus. The mean ITI was 20 s. Startle responses were measured for 100 ms after the onset of the pulse stimulus within trials. For each type of trial, startle amplitudes were averaged across 12 trials. In B2, the magnitude of PPI was calculated as a percent inhibition of the startle amplitude in the pulse-alone trial (treated as 100%) according to the formula: [1-(startle amplitude in prepulse-and-pulse trials/startle amplitude in pulse-alone trials)] 100%.
2.4.
3
Statistical analysis
In the first experiment, amplitudes of the startle reflex in B1 and in B2 as well as PPI were analyzed by repeated one-way ANOVA with treatment as a between-subjects factor and test day as a withinsubjects factor. PPI was analyzed by repeated two-way ANOVAs with treatment and prepulse intensity as between-subject factors and test day as within-subject factor. Startle habituation was analyzed by repeated two-way ANOVA with treatment and blocks (B1 and B3) as between-subject factors and test day as within-subject factor. In the second experiment, amplitudes of the startle reflex measured in B1 and in B2 were analyzed by a two-way ANOVA with chronic treatment (THC or VEH) and acute challenge treatment (Haloperidol or Saline) as between-subject factors. Startle habituation was analyzed by a repeated two-way ANOVA with blocks (B1 and B3) as within-subject factor and chronic and challenge treatments as between-subject factors. PPI were analyzed by a threeway ANOVA with chronic treatment, challenge treatment and prepulse intensity as between-subject factors. Post-hoc comparisons were performed using the LSD Fisher test. All analyses were performed using Statistica 11.0 (StatSoft Inc., USA). Data are expressed as mean7SEM of 8 animals per group.
3.
Results
3.1. Acute and chronic effects of THC on prepulse inhibition 3.1.1. Startle habituation As shown in Figure 1, comparing the startle response in the first block (B1) and the last block (B3) within sessions revealed a clear habituation effect (B14B3) both in the vehicle and in the THC-treated group. The main effect of blocks was highly significant (F1,42 = 118.37; po0.001) and was independent of the test day (block test day: F2,42 = 0.37; p40.05), indicating that startle reflex habituation was similar in sessions over the course of study. There was neither a main effect of treatment on habituation (F1,42 = 2.20; p40.05) nor any of its interactions (treatment habituation, F1,42 = 2.26; p40.05; treatment test day, F2,42 = 1.17; p40.05), indicating that habituation did not differ between THC-treated rats and their vehicletreated controls (meanvehicle-treated = 50.774.0%; meanTHCtreated = 52.373.90%). 3.1.2. Startle reactivity There was no main effect of group (F1,28 = 0.04; p40.05) or test day (F2,28 = 0.14; p40.05) on startle amplitudes in B1 (Figure 1A). Similarly, analysis of the startle amplitudes elicited on pulse alone trials in B2 did not reveal a significant main effect of group (F1,28 = 0.46; p40.05) or test day (F2,28 = 0.18; p40.05), indicating that THC treatment did not change startle reactivity when compared to vehicle and that this lack of treatment effect was preserved over the course of THC treatment (Figure 2A). 3.1.3. Prepulse inhibition Figure 2B–D shows the effect of acute and repeated administrations of vehicle or THC on PPI at different prepulse intensity levels (e.g. 75, 80 and 85 dB). A significant main effect of prepulse intensity on PPI was observed (F2,42 = 21.85; po0.001), with increasing prepulse intensities
Please cite this article as: Tournier, B.B., Ginovart, N., Repeated but not acute treatment with Δ9-tetrahydrocannabinol disrupts prepulse inhibition of the.... European Neuropsychopharmacology (2014), http://dx.doi.org/10.1016/j.euroneuro.2014.04.003
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B.B. Tournier, N. Ginovart
Figure 1 Acute and chronic effects of THC or its vehicle (VEH) on amplitude of the ASR (A) and startle habituation (B). Amplitude of the ASR during the first block and startle habituation were measured at 30 min following the first (day 1) and last (day 21) dose of a 21-days daily treatment with THC (1 mg/kg/day) or vehicle (VEH), and at 7 days after cessation of treatment (day 28). On each testing day, startle habituation (in %) was calculated by comparing the startle amplitude measured in a first (B1) and in a third (B3) block of five consecutive 120 dB pulse alone trial as follows: [1-(startle amplitude in B3/startle amplitude in B1)] 100%. Data represent mean7SEM of 8 animals per group. While there was a marked habituation of the startle response (main effect of block, F1,42 =118.37; po0.001), there was no significant group difference in startle habituation.
eliciting higher levels of PPI, which is a standard feature of PPI (Braff et al., 2001). Repeated two-way ANOVA also revealed a main effect of test day on PPI (F2,84 = 7.80; po0.05) that was dependent of the treatment group (treatment test day: F2,84 = 15.28; po0.001). There was also a significant group test day prepulse intensity interaction (F4,84 = 2.51; po0.05). LSD post-hoc tests revealed that the THC-treated group had significantly lower PPIs than the VEH-treated control group on the 21st day of chronic treatment but not on the first day of acute THC treatment at the prepulse intensities of 75 dB (po0.01; Figure 2B), 80 dB (po0.0001; Figure 2C) and 85 dB (po0.001; Figure 2D). Importantly, whatever the prepulse intensity used, group differences in PPI were abolished at 7 days following the cessation of treatment (Figure 2B–D).
3.2. Effect of haloperidol on THC-induced PPI deficits Two-way analysis of variance did not reveal significant effect of either chronic treatment with THC or acute challenge treatment with haloperidol on the startle reflex amplitude measured in B1 (THC treatment: F1,28 =1.00, p40.05; challenge treatment: F1,28 =2.23, p40.05). Similarly, there was also no significant effect of either chronic THC or acute haloperidol treatment on startle reactivity measured in B2 (THC treatment: F1,28 =0.36, p40.05; haloperidol treatment: F1,28 =2.27, p40.05; Figure 3A). However, startle response differed significantly between B1 and B3 (F1,28 =88.32; po0.001), independently of treatments (block chronic treatment challenge treatment: F1,28 =1.08, p40.05). Chronic treatment with THC or challenge treatment with haloperidol did not modify this startle habituation effect, as shown by the lack of effect of either treatment on habituation (chronic treatment: F1,28 =3.01, p40.05; challenge treatment: F1,28 =0.39, p40.05; chronic treatment challenge treatment: F1,28 =0.88, p40.05; Figure 3B).
The analysis performed on PPI showed significant main effects of both chronic THC (F1,84 =22.49; po0.001) and acute challenge with haloperidol (F1,84 =10.80, po0.01). Three-way ANOVA revealed a significant effect of prepulse intensities (F2,84 =34.33; po0.001) on PPI and a THC treatment haloperidol treatment prepulse intensity interaction (F2,84 =3.11; po0.05). Post-hoc analysis demonstrated that, similarly to the first experiment, chronic THC treatment led to significant PPI disruptions at the 75 dB (po0.001), 80 dB (po0.01) and 85 dB (po0.05) prepulse intensity levels (Figure 3C–E). Importantly, when compared to their respective saline-treated controls, an acute challenge dose of haloperidol had no effect on PPI in VEH-treated animals but significantly increased PPI in THC-treated animals at the 75 dB (po0.0001; Figure 3C) and 80 dB (po0.01; Figure 3D) prepulse intensity levels. Haloperidol (HAL) did completely reversed THC-induced PPI reductions at all prepulse intensities, as evidenced by the lack of significant difference between the THC+HAL and VEH +Saline groups at the 75 dB (p=0.54; Figure 3C), 80 dB (p=0.58; Figure 3D) and 85 dB (p=0.54; Figure 3E) prepulse intensities.
4.
Discussion
To our knowledge, this is the first study to investigate the effects of THC on PPI during acute and chronic drug treatment and following drug discontinuation, without potential confounders. Our findings show that repeated, but not acute, treatment with THC leads to deficits in sensorimotor gating that fully reverse within one week of THC discontinuation. Importantly, the disruptive effects of THC on PPI were observed in the absence of changes in the startle response and were reversed by the potent D2/3R antagonist haloperidol. This suggests that time-dependent neuroadaptations within the DA mesolimbic system may be involved in the PPI deficits that develop during chronic THC treatment.
Please cite this article as: Tournier, B.B., Ginovart, N., Repeated but not acute treatment with Δ9-tetrahydrocannabinol disrupts prepulse inhibition of the.... European Neuropsychopharmacology (2014), http://dx.doi.org/10.1016/j.euroneuro.2014.04.003
Repeated but not acute treatment with Δ9-tetrahydrocannabinol disrupts prepulse inhibition of the acoustic startle: Reversal by the dopamine D2/3 receptor antagonist haloperidol
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Figure 2 Acute and chronic effects of THC or its vehicle (VEH) on prepulse inhibition (PPI) of the acoustic startle reflex (ASR). The amplitude of the ASR during the second block (A) and PPI at prepulse intensities of 75 dB (B), 80 dB (C) and 85 dB (D) were measured at 30 min following the first (day 1) and last (day 21) dose of a 21-days daily treatment with THC (1 mg/kg/day) or vehicle (VEH), and at 7 days after cessation of treatment (day 28). Data are presented as mean7SEM of 8 animals per group. Significantly different from the respective VEH-treated group at nnpo0.01, and nnnpo0.001, using a two-way ANOVA followed by a LSD post-hoc test.
Our finding of a lack of effect of a single dose of 1-mg/kg THC on PPI is consistent with several (Boucher et al., 2007; Long et al., 2010b; Malone and Taylor, 2006), but not all (Long et al., 2010a; Nagai et al., 2006), previous studies which also failed to detect any significant effect of acute THC on sensorimotor performance in rodents, regardless of dosage. As mentioned in the introduction, previous work on the effects of chronic treatment with THC on PPI in rodents is limited to one study (Long et al., 2010a), in which no effect of THC was found. Similar chronic studies using the synthetic cannabinoid agonist WIN55,212-2 have however been reported but with inconsistent findings, with some studies reporting persistent PPI deficits (Schneider et al., 2005; Wegener and Koch, 2009), while others found no effect of the drug on PPI performance (Bortolato et al., 2005; Spano et al., 2010). Besides a strain- or speciesdependent effect of cannabinoids, it has been suggested that between-study difference in the age of initiation of cannabinoid treatment (i.e. adolescence vs. adult period) may be critical for PPI deficits to occur, with adolescent rats being more vulnerable than adults to the PPI disruptive effect of cannabinoid agonists (review in Schneider, 2008). However, another study challenged this view by showing
that chronic treatment with AM404, a selective reuptake and degradation inhibitor of the endogenous cannabinoid anandamide, led to PPI deficits when administered to adult mice (Fernandez-Espejo and Galan-Rodriguez, 2004). Moreover, it is noteworthy that most of the chronic cannabinoid research on PPI in rodents has been directed mainly toward WIN55,212-2, which is structurally unrelated to THC and shows different profiles of CB1R (Lauckner et al., 2005) and non-CB1R binding (Breivogel et al., 2001). Thus while the pharmacological effects produced by WIN55,212-2 and THC display considerable overlap, their different ability to activate different receptors and subsequent downstream signaling may hamper a direct and systematic extrapolation of the effects obtained with one agonist to the other. Consistent with this, different and sometimes even opposing effects of WIN55,212-2 and THC on cellular (Galanopoulos et al., 2011) and neurobehavioral (Patel and Hillard, 2006) responses have been reported. Contrasting with its lack of acute effect, our data showed that when administered daily for 21 consecutive days, relatively low doses of THC impaired PPI performance, suggesting that THC promotes neuroadaptations within the neural circuit regulating sensorimotor gating that develops
Please cite this article as: Tournier, B.B., Ginovart, N., Repeated but not acute treatment with Δ9-tetrahydrocannabinol disrupts prepulse inhibition of the.... European Neuropsychopharmacology (2014), http://dx.doi.org/10.1016/j.euroneuro.2014.04.003
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B.B. Tournier, N. Ginovart
Figure 3 Effect of an acute treatment with haloperidol (0.1 mg/kg; i.p.) on prepulse inhibition (PPI). The amplitude of the startle response (ASR) during the second block (A), startle habituation (B) and PPI at prepulse intensities of 75 dB (C), 80 dB (D) and 85 dB (E) were measured at 30 min following the last dose of a 21-days daily treatment with THC (1 mg/kg/day) or vehicle (VEH). Ten minutes prior to the last treatment dose, both the VEH-treated and THC-treated rats received an i.p. administration of either haloperidol (HAL; 0.1 mg/kg) or saline vehicle (n =8). Data are presented as mean7SEM of 8 animals per group. Significantly different from the VEH-Saline group at npo0.05, nnpo0.01, nnnpo0.001 and significantly different from the THC–Saline group at ⌘⌘⌘ po0.01, ⌘⌘po0.01 using a three-way ANOVA followed by a LSD post-hoc test.
during the course of repeated drug administration. However, chronic THC only had a transient detrimental effect on sensorimotor gating function as, while observed at 30 min after the last dose, PPI deficits had completely recovered within 7 days after treatment had ceased. These data suggest that the functional alterations produced by THC are quickly reversible following treatment cessation and may be related to a drug residue effect during the few hours to the few days following THC dosing rather than to a permanent neurotoxic effect of the drug. Indeed, due to its high lipophilicity and sequestration in fat, the tissue elimination half-life of THC is slow, being estimated to be from about 16 h (Nahas, 1972) to as long as 5 days (Kreuz and Axelrod, 1973) in rats. Our data also suggest that the duration of time elapsed between last cannabis use and PPI measurement is critical for measuring cannabis-related effects on sensorimotor gating and may be a main reason for the inconsistent findings previously reported regarding the influence of cannabis consumption on PPI in chronic human users. Indeed, the duration of cannabis abstinence period prior to PPI testing widely differed between previous
studies, ranging from practically none in studies reporting cannabis-related PPI deficits (Kedzior and Martin-Iverson, 2006; Scholes and Martin-Iverson, 2009; Scholes-Balog and Martin-Iverson, 2011) to a few hours to a few days in studies reporting no alteration (Mathias et al., 2011; Quednow et al., 2004). Moreover, a time-dependent decreasing effect of THC on PPI following discontinuation would be consistent with, and may shed light on, the correlation previously reported between PPI alterations and the recency of cannabis use in chronic users (Scholes and Martin-Iverson, 2009). As abnormalities in pre-attentive information processing, as measured by PPI deficits, are thought to contribute to impaired cognitive functioning, the time-dependency of THC-induced PPI alterations observed here is consistent with studies indicating that chronic cannabis consumption in human is associated with a decline in cognitive performance that develop gradually with prolonged cannabis use and worsen with years of use (Solowij et al., 2002), but last only for a limited period beyond the immediate hours of intoxication (Schreiner and Dunn, 2012). Taken together with prior human studies, our results do not support the
Please cite this article as: Tournier, B.B., Ginovart, N., Repeated but not acute treatment with Δ9-tetrahydrocannabinol disrupts prepulse inhibition of the.... European Neuropsychopharmacology (2014), http://dx.doi.org/10.1016/j.euroneuro.2014.04.003
Repeated but not acute treatment with Δ9-tetrahydrocannabinol disrupts prepulse inhibition of the acoustic startle: Reversal by the dopamine D2/3 receptor antagonist haloperidol idea of a long-term persistence of neuropsychological dysfunctioning following cessation of chronic cannabis use. A large body of evidence indicates that the central DA system contributes to the regulation of PPI, although there is also evidence for a role of the serotonin and glutamatergic system as well (Geyer et al., 2001; Swerdlow et al., 2001). In rodents, PPI is disrupted by acute treatment with direct or indirect DA agonists (Mansbach et al., 1988), as well as with selective D2-receptor (D2R) agonists (Weber et al., 2010), and these effects can be reversed by D2R antagonists. Moreover, while the activation of D2R in the mesolimbic DA system, especially in the nucleus accumbens (Wan and Swerdlow, 1993), appears essential to the DAergic regulation of PPI, emerging evidence demonstrates that stimulation of accumbal D3R also contributes to this effect (Chang et al., 2012). The present study showed that the PPI deficit induced by chronic THC treatment can be reversed by a low, non-cataleptic dose, of the D2/3R antagonist haloperidol, suggesting that an overactivity of D2/3R-mediated DA transmission in the mesoaccumbal system likely contributes to the gating-disruptive effects of THC. This hypothesis is consistent with recent data from our group showing that chronic THC increases the density and functional sensitivity of D2/3R in the nucleus accumbens (Ginovart et al., 2012). In this latter study, the hypersensitization of postsynaptic D2/3R in nucleus accumbens was accompanied by a concomitant hypoactivity of presynaptic DA signaling, making it difficult to predict the overall net effect of THC treatment on DA transmission. The current results support the view that chronic THC produces a net facilitation of D2/3R-mediated DA signaling in the mesoaccumbal system. Collectively, these findings show considerable overlap with the psychopathogical and neurochemical changes associated with schizophrenia. PPI disruptions have been widely reported in schizophrenia (review in Braff et al., 2001). Moreover, the symptoms of psychosis are thought to result from an excess of DA signaling in the mesolimbic system (Davis et al., 1991), and two independent meta-analyses provide evidence for an increased density of striatal D2/3R in schizophrenia (Kestler et al., 2001; Weinberger and Laruelle, 2002), lending support to the view that an overactivity of D2/3R may be critically involved in the PPI deficits seen in schizophrenia (Swerdlow et al., 1991). The overlap between PPI and D2/3R abnormalities induced by chronic THC and those previously reported in schizophrenia may improve our understanding of the mechanism underlying the propsychotic action of THC. In summary, our data indicate that chronic but not acute exposure to THC leads to the development of PPI deficits that can be reversed by D2/3R blockade, indicating that an overactivity of D2/3R function contributes to the gating-disruptive effects of the drug. THC-induced PPI deficits were fully normalized within the first week after THC discontinuation, indicating that the drug only has transient detrimental effects on sensorimotor gating ability. These findings add to the emerging evidence that chronic THC exposure increases DA function in brain, highlighting a potential role for D2/3R in the propsychotic effect of the drug.
Role of funding sources Funding for this study was provided by Swiss National Science Foundation (SNFS) grant 31003 A-122352 to N.G.; the SNFS had no
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further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.
Contributors B.B.T. performed behavioral tests, statistical analyses, and contributed to the first draft of the manuscript. N.G. wrote the protocol, supervised the experimental design and execution, and wrote the manuscript. All authors read and approved the final manuscript.
Conflict of interest The authors certify that there is no actual or potential conflict of interest in relation to this article.
Acknowledgment None.
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